MX2011004924A - Salts of fingolimod. - Google Patents
Salts of fingolimod.Info
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/08—Acetic acid
- C07C53/10—Salts thereof
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/122—Propionic acid
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/08—Malonic acid
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- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
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- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
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- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/04—Monocyclic monocarboxylic acids
- C07C63/06—Benzoic acid
- C07C63/08—Salts thereof
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Abstract
The present invention relates to salts, polymorphs and hydrates of 2-Amino-2-[2-(4-C2-20-alky-phenyl)ethyl]propane~1,3~ diol, and to the use thereof, in particular in the treatment or prevention of various autoimmune conditions.
Description
FINGOLIMOD SALTS
The present invention relates to salts, for example, to crystalline salts, of the compound FTY720, and to the use thereof.
In European Patent Number EP-A-0627406, 2-amino-2- [2- (4-alkyl-2 to 20 carbon atoms-f-enyl) -ethyl] -propane-1, 3 compounds are disclosed. -diol, the relevant disclosure of which is incorporated herein as a reference. Based on the observed activity, the compounds have been found to be useful as immunosuppressants. In accordance with the foregoing, the compounds may be useful in the treatment or prevention of different autoimmune conditions, including multiple sclerosis. A particular compound of this class is FTY720 (2-amino-2- [2- (4-octyl-phenyl) -ethyl] -propane-1,3-diol, fingolimod), which can be obtained in the form of the free base or a hydrochloride salt. The structure of the FTY720 is shown below:
According to the present invention, a crystalline salt of FTY720 is provided, wherein the salt is selected from the tartrate, lactate, benzoate, succinate, malonate, acetate and propionate salts, and the salt is optionally crystalline.
In one embodiment, the salt is selected from the salts of
tartrate, lactate, benzoate, succinate and malonate.
In another embodiment, the salt is selected from the tartrate, lactate, succinate and malonate salts.
In one embodiment, the salt is a tartrate salt.
In a specific embodiment, the salt is a tartrate salt characterized by an X-ray powder diffraction pattern having peaks, at least two, preferably at least four, and most preferably all, of the following values 2-theta: approximately 3.1, 19.3, 21.7, 9.6, 17.2, 6.4, 22.6 and 20.8 degrees 2-theta. The peaks at these 2-theta values can have the following relative intensities: 3.1 (strong), 19.3 (weak), 21.7 (weak), 9.6 (weak), 17.2 (weak), 6.4 (weak), 22.6 (weak), and 20.8 (weak). In a particular embodiment, the salt is a tartrate salt characterized by an X-ray powder diffraction pattern substantially corresponding to that shown in Figure 1.
In one embodiment, the salt is a lactate salt.
In a specific embodiment, the salt is a lactate salt characterized by an X-ray powder diffraction pattern having peaks, at least two, preferably at least four, and most preferably all, of the following values 2-theta: 4.3, 8.7, 20.8, 13.1, 10.3, 18.8, 8.1, 21.6, 21.9 and 19.6 degrees 2-theta. The peaks at these 2-theta values can have the following relative intensities: 4.3 (strong), 8.7 (medium), 20.8 (medium), 13.1 (medium), 10.3 (weak), 18.8 (weak), 8.1 (weak), 21.6 (weak), 21.9 (weak), and 19.6 (weak). In a particular modality, the
salt is a lactate salt characterized by an X-ray powder diffraction pattern substantially corresponding to that shown in Figure 2.
In one embodiment, the salt is a benzoate salt.
In a specific embodiment, the salt is a benzoate salt characterized by an X-ray powder diffraction pattern with peaks, at least two, preferably at least four, and most preferably all of the following values. -theta: 3.7, 7.5, 18.7, 19.8, 15.2, 19.4, 19.9, 6.0 and 21.9 degrees 2-theta. The peaks at these 2-theta values can have the following relative intensities: 3.7 (strong), 7.5 (medium), 18.7 (weak), 19.8 (weak), 15.2 (weak), 19.4 (weak), 19.9 (weak), 6.0 (weak), and 21.9 (weak). In a particular embodiment, the salt is a benzoate salt characterized by an X-ray powder diffraction pattern substantially corresponding to that shown in Figure 3.
In one embodiment, the salt is a succinate salt.
In a specific embodiment, the salt is a succinate salt characterized by an X-ray powder diffraction pattern having peaks, at least two, preferably at least four, and most preferably all, of the following values 2-theta: 3.2, 19.8, 20.7, 23.3, 26.2, 9.8, 19.4, 24.5, 33.4, 26.6 and 22.6 degrees 2-theta. The peaks at these 2-theta values can have the following relative intensities: 3.2 (strong), 19.8 (medium), 20.7 (weak), 23.3 (weak), 26.2 (weak), 9.8 (weak), 19.4 (weak), 24.5 (weak), 33.4 (weak), 26.6 (weak), and 22.6 (weak). In a modality
in particular, the salt is a succinate salt characterized by an X-ray powder diffraction pattern substantially corresponding to that shown in Figure 4.
In one embodiment, the salt is a malonate salt.
In a specific embodiment, the salt is a malonate salt characterized by an X-ray powder diffraction pattern having peaks, at least two, preferably at least four, and most preferably all, of the following values 2-theta: 2.5, 5.2, 8.0, 16.2, 17.0, 20.4 degrees 2-theta. The peaks at these 2-theta values can have the following relative intensities: 2.5 (strong), 5.2 (weak), 8.0 (weak), 16.2 (weak), 17.0 (weak), 20.4 (weak). In a particular embodiment, a malonate salt is provided characterized by an X-ray powder diffraction pattern substantially corresponding to that shown in Figure 5.
In one embodiment, the salt is an acetate salt.
In a specific embodiment, the salt is an acetate salt characterized by an X-ray powder diffraction pattern having peaks, at least two, preferably at least four, and most preferably all, of the following values 2-theta: 4.8, 8.4, 10.1, 11.5, 15.2, 17.7, 19.3, 20.1, 21.5, 21.9, 24.0, 25.4, degrees 2-theta. The peaks at these 2-theta values can have the following relative intensities: 4.8 (strong), 8.4 (weak), 10.1 (medium), 11.5 (weak), 15.2 (medium), 17.7 (weak), 19.3 (weak), 20.1 (weak), 21.5 (weak), 21.9 (weak), 24.0 (weak), 25.4 (medium), 30.8
(weak). In a particular embodiment, an acetate salt is provided characterized by an X-ray powder diffraction pattern substantially corresponding to that shown in Figure 6.
In one embodiment, the salt is a propionate salt.
In a specific embodiment, the salt is a propionate salt characterized by an X-ray powder diffraction pattern having peaks, at least two, preferably at least four, and most preferably all, of the following values 2-theta: 4.8, 8.4, 9.8, 14.7, 16.8, 17.6, 19.7, 20.2, 22.6, 24.8, 29.8 degrees 2-theta. The peaks at these 2-theta values can have the following relative intensities: 4.8 (strong), 8.4 (weak), 9.8 (medium), 14.7 (weak), 16.8 (weak), 17.6 (weak), 19.7 (weak), 20.2 (weak), 22.6 (weak), 24.8 (weak), 29.8 (weak). In a particular embodiment, a propionate salt characterized by an X-ray powder diffraction pattern substantially corresponding to that shown in Figure 7 is provided.
Conveniently, the different salt forms of the invention may have one or more desirable properties, compared to the free base form or the hydrochloride form of the FTY720. For example, the salts may be more stable and of better quality than the free base, in particular during storage and distribution. In addition, the salts may have a high degree of dissociation in water and, consequently, a substantially improved water solubility. The present salts may also be convenient in that they do not show absorption or
measurable water loss.
The crystalline forms can be characterized by the major peaks of an X-ray powder diffraction spectrum, as illustrated in the Examples herein. The crystalline forms may also differ with respect to their thermodynamic stability, in their physical parameters, such as the pattern of absorption in an infrared (IR) spectroscope or phase transition signals in differential scanning calorimetry (DSC). The salts of the present invention are preferably in a substantially pure crystalline form. The term "substantially pure", as used herein, includes reference to crystalline forms of more than 90 percent, more preferably, 95 percent, more preferably, 96 percent, most preferably, 97 percent. one hundred, more preferably, 98 percent, more preferably, 99 percent polymorphic purity as determined, for example, by X-ray powder diffraction, Raman spectroscopy or infrared (IR) spectroscopy.
The salts of the invention may be in the form of solvates, including hydrates, and may exhibit polymorphism.
The salts of the present invention can be synthesized from the free base by conventional chemical methods. In general terms, these salts can be prepared by reacting the free base form of FTY720 with the appropriate acid in water or in an organic solvent, or in a mixture of the two. In many cases, a non-aqueous medium can be used, for example,
ethyl acetate, ethanol or isopropanol. The FTY720 and the acid are combined in the desired stoichiometric ratio, for example, 1: 1 or 1: 2. The salt can then be left or induced to crystallize or to form an amorphous solid, optionally before crystallization. The solid salt can then be dried, for example, by heating under reduced pressure. By way of illustration, and without limitation, the different salt forms of the invention can be obtained according to the procedures given in the Examples herein.
Pharmaceutical formulations comprising a crystalline salt of the invention are also provided. A pharmaceutical formulation of the invention preferably contains 0.01 to 20 weight percent of the salt, more preferably 0.1 to 10 weight percent, eg, 0.5 to 5 weight percent, based on the total weight of the formulation.
The pharmaceutical formulation can be a solid pharmaceutical composition in a form suitable for oral administration, for example, a tablet or capsule. The composition can be made in a conventional manner, for example, by mixing a salt of the invention with a pharmaceutically acceptable carrier or diluent.
In a particular embodiment, the formulation is a solid pharmaceutical composition comprising a salt of the invention and a sugar alcohol. Compositions of this type are disclosed in International Publication Number WO
2004/089341, the content of which is incorporated herein by reference. The solid compositions disclosed in this publication are in particular suitable for oral administration of the salts of the present invention. The compositions provide a means of convenient systemic administration of the compounds, do not suffer from the disadvantages of liquid formulations for injection or oral use, and have good physical-chemical and storage properties. In particular, the compositions of the present invention can show a high level of uniformity in the distribution of the compound throughout the composition, as well as high stability. The compositions, therefore, can be made in automated high-speed equipment and, therefore, do not require manual encapsulation.
The sugar alcohol may act as a diluent, carrier, filler or bulking agent, and in a suitable manner may be mannitol, maltitol, inositol, xylitol or lactitol, preferably a substantially non-hygroscopic sugar alcohol, eg, mannitol (D-mannitol) A single sugar alcohol, or a mixture of two or more sugar alcohols, for example, a mixture of mannitol and xylitol, for example, may be used in a ratio of 1: 1 to 4.1.
In a particularly preferred embodiment, the sugar alcohol is prepared from a spray-dried composition, for example, a mannitol composition, which has a high specific surface area. The use of this type of mannitol composition
it can help promote a uniform distribution of the compound throughout the mannitol in the composition. A higher surface area can be achieved by providing a sugar alcohol preparation, for example, mannitol, consisting of particles having a smaller average size and / or a rougher surface on each particle. It has also been found that the use of a spray-dried sugar alcohol, for example, mannitol, for example, with an average particle size of 300 microns or less, improves the possibility of compression and hardness of the tablets formed from of the composition.
Preferably the surface area of a single point of the sugar alcohol preparation, for example, mannitol, is from 1 to 7 m2 / gram, for example, from 2 to 6 m2 / gram or from 3 to 5 m2 / gram. The mannitol preparation can suitably have an average particle size of 100 to 300 microns, for example, 150 to 250 microns, and a bulk density of 0.4 to 0.6 grams / milliliter, for example, 0.45. at 0.55 grams / milliliter. A mannitol of a suitable high surface area is Parteck M200, commercially available from E. Merck.
The composition preferably contains from 75 to 99.99 percent by weight of the sugar alcohol, more preferably from 85 to 99.9 percent, for example, from 90 to 99.5 percent by weight, based on the total weight of the composition.
The composition preferably also comprises a lubricant. Suitable lubricants include stearic acid,
magnesium stearate, calcium stearate, zinc stearate, palm glyceryl stearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oil, such as hydrogenated castor oil (for example, Cutina® or Lubriwax® 101), mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer, or a mixture of any of the foregoing. Preferably, the lubricant comprises magnesium stearate, hydrogenated castor oil, or mineral oil. Colloidal silicon dioxide and polyethylene glycol are the least preferred as the lubricant.
The composition preferably contains 0.01 to 5 weight percent of a lubricant, more preferably, 1 to 3 weight percent, eg, about 2 weight percent, based on the total weight of the composition.
The composition may comprise one or more additional excipients, such as vehicles, binders or diluents. In particular, the composition may comprise microcrystalline cellulose (eg, Avicel®), methyl-cellulose, hydroxy-propyl-cellulose, hydroxy-propyl-methyl-cellulose, starch (eg, corn starch) or calcium diphosphate, preference in an amount of 0.1 to 90 percent by weight, for example, 1 to 30 percent by weight, based on the total weight of the composition. When a binder is used, for example, microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, preferably
it is included in an amount of 1 to 8 percent, for example, 3 to 6 percent by weight, based on the total weight of the composition. The use of a binder increases the strength of the granule of the formulation, which is particularly important for fine granulations. Particular preference is given to microcrystalline cellulose and methyl cellulose, where a high hardness of the tablet and / or a longer disintegration time is required. Hydroxypropyl cellulose is preferred, where faster disintegration is required. When appropriate, xylitol can also be added as an additional binder, for example, in addition to microcrystalline cellulose, for example, in an amount of up to 20 weight percent of the sugar alcohol, for example, xylitol.
In one embodiment, the composition further comprises a stabilizer, preferably glycine-HCl or sodium bicarbonate. The stabilizer may be present in an amount, for example, from 0.1 to 30 percent, preferably from 1 to 20 percent by weight.
The composition may be in the form of a powder, granule or agglomerates, or in a unit dosage form, for example, as a tablet or capsule. The compositions of the present invention are well suited for encapsulation in an orally administrable capsule shell, in particular a hard gelatin shell.
In an alternative way, the compositions can be compacted into tablets. The tablets can optionally be coated, for example, with talc or with a coating of
polysaccharide (for example, cellulose) or hydroxy-propyl-methyl-cellulose.
When a pharmaceutical capsule is in a unit dosage form, each unit dosage, for example, may contain from about 0.5 to about 10 milligrams of a salt of the invention.
The compositions of the invention may exhibit good stability characteristics, as indicated by conventional stability studies, for example, having a shelf life stability of up to one, two or three years, and even longer. Stability characteristics can be determined, for example, by measuring the decomposition products by HPLC analysis after storage for particular times, at particular temperatures, for example, at 20 ° C, at 40 ° C, or at 60 ° C. ° C.
The pharmaceutical compositions of the present invention can be produced by conventional processes, for example, by conventional mixing, granulating, sugar coating, dissolving, or lyophilizing processes. The methods that can be employed are known in the art, for example, those described in L. Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd Edition, 1986, H Sucker et al., Pharmazeutische Technologie, Thieme, 1991, Hagers. Handbuch der pharmazeutischen Praxis, 4th Edition. (Springer Verlag, 1971), and Remington's Pharmaceutical Sciences, 13th Edition, (Mack Publ., Co., 1970) or later editions.
In one embodiment, the pharmaceutical composition is produced by a process comprising:
(a) mixing a salt of the invention with a sugar alcohol;
(b) grinding and / or granulating the mixture obtained in (a); Y
(c) mixing the milled and / or granulated mixture obtained in (b) with a lubricant.
By employing this process, a preparation having a good level of content and mixing uniformity (ie, a substantially uniform distribution of the salt throughout the composition), dissolution time and stability is obtained.
The salt can optionally be micronised and / or pre-sieved, for example, with a mesh size of 400 to 500 microns, before step (a) in order to remove the lumps. The mixing step (a) may comprise, in a suitable manner, mixing the salt and the sugar alcohol, for example, mannitol, in any suitable blender or mixer, for example, from 100 to 400 revolutions.
The process can be carried out by dry mixing the components. In this embodiment, the grinding step (b) may comprise, in a suitable manner, passing the mixture obtained in (a) through a screen, which preferably has a mesh size of 400 to 500 microns. Process step (a) may comprise the step of mixing the total amount of the salt first with a low amount of sugar alcohol, for example, from 5 to 25 weight percent of the total weight of the sugar alcohol, with the object to form a pre-mix. Subsequently,
the remaining amount of sugar alcohol is added to the pre-mix. Step (a) may also comprise the step of adding a binder solution, for example, methyl cellulose and / or xylitol, for example, an aqueous solution, to the mixture. Alternatively, the binder is added to the dry mix, and water is added to the granulation step.
The ground mixture obtained in (b) can optionally be mixed once more before mixing with the lubricant. The lubricant, for example, magnesium stearate, is preferably pre-sieved, for example, with a sieve of 800 to 900 microns, before mixing.
In an alternative way, a wet granulation process is employed. In this embodiment, the salt is preferably first mixed dry with the desired sugar alcohol, for example, mannitol, and the obtained sugar alcohol / salt mixture is then dry blended with a binder, such as hydroxypropyl cellulose or hydroxy-propyl-methyl-cellulose. Then water is added, and the mixture is granulated, for example, using an automated granulator. The granulation is then dried and ground.
If it is advisable, an additional amount of binder can be added in step (c) to the mixture obtained in (b).
The process may comprise an additional step of tabletting or encapsulation of the mixture obtained in (c), for example, in a hard gelatin capsule using an automated encapsulation device. The capsules can be colored or
mark to impart an individual appearance, and to make them instantly recognizable. The use of dyes can serve to improve the appearance, as well as to identify the capsules. The dyes suitable for use in pharmacy typically include carotenoids, iron oxides, and chlorophyll. Preferably, the capsules of the invention are marked using a code.
The salts of the invention may be useful in:
a) the treatment and prevention of rejection of organ or tissue transplantation, for example, for the treatment of recipients of heart, lung, heart-lung, liver, kidney, pancreas, skin or cornea transplants, and prevention of graft-versus-host disease, such as occurs sometimes following bone marrow transplantation; in particular in the treatment of acute or chronic rejection of allo- and xenograft, or in the transplantation of insulin-producing cells, for example, pancreatic islet cells; Y
b) the treatment and prevention of autoimmune disease or inflammatory conditions, for example, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I or II diabetes and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata and others, allergic diseases, for example, allergic asthma, atopic dermatitis, rhinitis / allergic conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally with
underlying aberrant reactions, eg, inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lesion of the lung, inflammatory lesion of the liver, inflammatory glomerular lesion, atherosclerosis, osteoarthritis, irritant contact dermatitis and other eczematous dermatitis, dermatitis seborrheic, skin manifestations of immunologically mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.
For the above uses, the dosage required, of course, will vary depending on the mode of administration, the particular condition to be treated, and the desired effect. In general, satisfactory results are reported in daily dosages of from about 0.1 to about 100 milligrams / kilogram of body weight. An indicated daily dosage in the higher mammal, for example, in humans, is in the range of about 0.5 milligrams to 2000 milligrams, conveniently administered, for example, in divided doses up to four times a day or in a delayed form.
The salts may be administered by any appropriate route, for example, orally, for example, in the form of a tablet or capsule, topically or parenterally, for example, intravenously. Pharmaceutical compositions comprising a salt of the invention in association with at least one pharmaceutically acceptable carrier or diluent, can be made in a conventional manner, by mixing with a
pharmaceutically acceptable carrier or diluent. The unit dosage forms for oral administration contain, for example, from about 0.1 milligrams to about 500 milligrams of active substance.
The salts may be administered as the sole active ingredient, or together with other drugs in immunomodulatory regimens, or other anti-inflammatory agents, for example, for the treatment or prevention of acute or chronic allograft rejection, or inflammatory or autoimmune For example, they can be used in combination with calcineurin inhibitors, for example, cyclosporin A, cyclosporin G, FK-506, ABT-281, ASM 981; an mTOR inhibitor, for example, rapamycin, 40-O- (2-hydroxy) -ethyl-rapamycin, CCI779, ABT578 or AP23573 etc .; corticosteroids; cyclophosphamide; azathioprene; methotrexate; another S1P receptor agonist, for example, FTY 720 or an analogue thereof; leflunomide or analogues thereof; mizoribin; mycophenolic acid; mycophenolate-mofetil; 15-deoxy-spergualin or analogues thereof; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD11 / CD18, CQ7, CD25, CD27, B7, CD40, CD45, CD58, CD137, ICOS, CD150 (SLAM), OX40, 4-1BB or their ligands, for example, CD154; or other immunomodulatory compounds, for example, a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, for example,
at least one extracellular portion of CTLA4 or a mutant thereof bound to a protein sequence that is not CTLA4, eg, CTLA4lg (eg, designated as ATCC 68629) or a mutant thereof, eg, LEA29Y, or other inhibitors of adhesion molecules, for example, mAbs or low molecular weight inhibitors, including LFA-1 antagonists, selectin antagonists, and VLA-4 antagonists.
When a salt is administered in conjunction with another immunomodulatory or anti-inflammatory agent, the dosages of the immunomodulatory or anti-inflammatory agent co-administered will, of course, vary depending on the type of co-drug employed, the condition to be treated , etc.
The present invention, therefore, provides:
1. A method for the treatment or prevention of rejection of organ or tissue transplantation, which comprises administering to a subject, a therapeutically effective amount of a crystalline salt of the invention.
2. A method for the treatment or prevention of an autoimmune disease or an inflammatory condition, which comprises administering to a subject, a therapeutically effective amount of a crystalline salt of the invention.
3. A salt of the invention, for example, a crystalline salt of the invention, for use as a pharmaceutical product.
4. A pharmaceutical composition, which comprises a salt of the invention, for example, a crystalline salt of the invention, and a
diluent or pharmaceutically acceptable vehicle.
5. The use of a salt of the invention, for example, a crystalline salt of the invention, for the preparation of a medicament, for example, in a method as disclosed above.
6. A pharmaceutical combination, which comprises: (a) a salt of the invention, for example, a crystalline salt of the invention, and (b) a second drug substance, this second drug substance being suitable for prevention or treatment of a condition described above.
7. A method as defined above, which comprises the co-administration, for example, in a concomitant or sequential manner, of: (a) a crystalline salt of the invention, and (b) a second drug substance, this being second drug substance suitable for the prevention or treatment of a condition described above.
The following examples illustrate the invention. In Examples 1 to 29, references to compound A, FTY720, or FTY720 hydrochloride salt, should be taken to include reference to any of the different salts of the present invention.
Example 1
The micronized compound A, for example, the hydrochloride salt of 2-amino-2- [2- (4-octyl-phenyl) -ethyl] -propane-1,3-diol (FTY720), is screened, and 116.7 grams of the sifted compound are mixed with 9683.3 grams of a microcrystalline cellulose agent. The mixture is then ground in a Frewitt MGI device (Key International
Inc. USA), using a 30 mesh screen. The magnesium stearate is sieved using a 30 mesh screen, and 200 grams of the sifted compound is mixed with the FTY720 mixture to produce a composition of the product.
The composition of the product is then compacted in a tablet press, using a 7 millimeter die, to form tablets of 120 milligrams, each containing:
Compound A, for example, FTY720 * 1.4 mg
Microcrystalline cellulose, by
example, Avicel PH 102 116.2 mg
Magnesium stearate 2.4 mg
Total 120 mg
* 1 milligram of compound A in free form is equivalent to 1.12 milligrams of FTY720.
Example 2
In a further example, the process of Example 1 is repeated, except that the magnesium stearate is replaced by Cutina® (hydrogenated castor oil).
Example 3: FTY720 tartrate
The tartrate salt was then analyzed by X-ray powder diffraction (XRPD). In this and the following examples, X-ray powder diffraction patterns (XRPD) were recorded between 2 ° and 35 ° (2-theta) with Cu Ka radiation using a Scintag X1 diffraction system. X-ray powder diffraction (XRPD) of variable temperature and variable humidity was carried out
using the Scintag XDS 2000 system equipped with a temperature and humidity control unit.
The X-ray powder diffraction pattern (XRPD) of the FTY720 tartrate is shown in Figure 1, with the significant peaks given below:
Example 4: FTY720 lactate
The X-ray powder diffraction pattern (XRPD) of the lactate of FTY720 is shown in Figure 2, with the significant peaks given below:
2-Theta (degrees) Space-d (Á) Relative Intensity
4. 3 20,493 Strong
8. 7 10,183 Media
20. 8 4.272 Average
13. 1 6,768 Media
10. 3 8.587 Weak
18. 8 4.717 Weak
8. 1 10.878 Weak
21. 6 4.102 Weak
21. 9 4.051 Weak
19. 6 4,527 Weak
Example 5: Benzoate of FTY720
The X-ray powder diffraction pattern (XRPD) of the FTY720 benzoate is shown in Figure 3, with the significant peaks given below:
2-Theta (degrees) Space-d (Á) Relative Intensity
3. 7 23,816 Strong
2-Theta (degrees) Space-d (Á) Relative Intensity
7. 5 11.762 Average
18. 7 4.743 Weak
19. 8,490 Weak
15. 2 5.842 Weak
19. 4 4.583 Weak
19. 9,448 Weak
6. 0 14.709 Weak
21. 9 4.051 Weak
Example 6: FTY720 Succinate (2: 1)
The X-ray powder diffraction pattern (XRPD) of the FTY720 succinate (2: 1) is given in Figure 4, with the significant peaks given below:
2-Theta (degrees) Space-d (Á) Relative Intensity
3. 2 27,952 Strong
19. 8,476 Average
20. 7 4.294 Weak
2-Theta (degrees) Space-d (Á) Relative Intensity
23. 3 3.810 Weak
26. 2 3.403 Weak
9. 8 8.986 Weak
19. 4 4,571 Weak
24. 5 3.626 Weak
33. 4 2,681 Weak
26. 6 3,354 Weak
22. 6 3.929 Weak
Example 7: Malonate of FTY720 (2: 1)
The free base of FTY720 (1.63 mmol) was dissolved in i-PrOH (6 milliliters) at 82 ° C. Then a solution of malonic acid (0.815 millimoles) in i-PrOH (1 milliliter) was added at 82 ° C. Immediately after the addition, the product began to crystallize. The suspension was cooled to room temperature. The product was collected by filtration, and washed with i-PrOH (2 milliliters). After drying at 50 ° C, the product was obtained as white crystals in 92.3 percent yield.
In an alternative procedure, the free base of FTY720 (2.27
millimoles) was dissolved in ethyl acetate (16 milliliters) from 88 ° C to 90 ° C. Then a solution of malonic acid (1.14 mmol) in ethyl acetate (3 milliliters) was added at 75 ° C, upon which the product started to crystallize immediately after the addition. The resulting suspension was cooled to room temperature. The product was collected by filtration, and washed with ethyl acetate (2 milliliters). After drying at 50 ° C, the product (788 milligrams) was obtained as white crystals.
The X-ray powder diffraction diagram (XRPD) of the FTY720 malonate is given in Figure 5, with the significant peaks given below:
Example 8: Acetate of FTY720
The free base of FTY720 (1.63 millimoles) was dissolved in i-PrOH
(6 milliliters) at 82 ° C. Then a solution of acetic acid (1.79 equivalents) in i-PrOH (1 milliliter) was added at 82 ° C. The clear solution was cooled to room temperature, upon which the product crystallized. The resulting suspension was stirred for an additional 15 minutes, the product was collected by filtration, and washed with i-PrOH (4 milliliters). After drying at 50 ° C, the crude product was obtained as white crystals in 83 percent yield. The product was recrystallized from a mixture of i-PrOH / acetic acid in a 90.6 percent yield.
In an alternative procedure, the free base of FTY720 (2.27 mmol) was dissolved in ethyl acetate (16 milliliters) from 88 ° C to 90 ° C. Then a solution of acetic acid (2.5 equivalents) in ethyl acetate (3 milliliters) was added at 75 ° C, over which, the product started to crystallize immediately after the addition. The resulting suspension was cooled to room temperature. The product was collected by filtration, and washed with ethyl acetate (2 milliliters). After drying at 50 ° C, the product was obtained as white crystals in 99.4 percent yield.
The X-ray powder diffraction diagram (XRPD) of the FTY720 malonate is given in Figure 6, with the significant peaks given below:
2-Theta (degrees) Relative Intensity
4. 8 Strong
2-Theta (degrees) Relative Intensity
8. 4 Weak
10. 1 Average
11. 5 Weak
15. 2 Average
17. 7 Weak
19. 3 Weak
20. 1 Weak
21. 5 Weak
21. 9 Weak
24. 0 Weak
25. 4 Average
30. 8 Weak
Example 9: FTY720 Propionate
The free base of FTY720 (1.63 mmol) was dissolved in i-PrOH (6 milliliters) at 82 ° C. Then a solution of propionic acid (1.79 equivalents) in i-PrOH (1 milliliter) was added at 82 ° C. The
The clear solution was cooled to room temperature, over which, the product crystallized. The resulting suspension was stirred for an additional 15 minutes, the product was collected by filtration, and washed with i-PrOH (2 milliliters). After drying at 50 ° C, the crude product was obtained as white crystals in 68 percent yield. The product was recrystallized from a mixture of i-PrOH / propionic acid in a 90.6 percent yield.
In an alternative procedure, the free base of FTY720 (2.27 mmol) was dissolved in ethyl acetate (16 milliliters) from 88 ° C to 90 ° C. Then a solution of propionic acid (2.5 equivalents) in ethyl acetate (3 milliliters) was added at 70 ° C, upon which, the product started to crystallize immediately after the addition. The resulting suspension was cooled to room temperature. The product was collected by filtration, and washed with ethyl acetate (2 milliliters). After drying at 50 ° C, the product was obtained as white crystals in 96.9 percent yield.
The X-ray powder diffraction pattern (XRPD) of the FTY720 propionate is given in Figure 7, with the significant peaks given below:
2-Theta (degrees) Relative Intensity
4. 8 Strong
8. 4 Weak
2-Theta (degrees) Relative Intensity
9. 8 Average
14. 7 Weak
16. 8 Weak
17. 6 Weak
19. 7 Weak
20. 2 Weak
22. 6 Weak
24. 8 Weak
29. 8 Weak
Example 10: Solubility Study
The solubilities of different salts were evaluated, and are given in the following table (approximate values at 25 ° C, grams / 100 milliliters percent):
Base ClorhiTar- Lac- BenSucci- Solvent
Free drato trata tato zoato nato
HCI 0.1 N > 2 > 2 > 2
Base ClorhiTar- Lac- BenSucci- Solvent
Free drato trata tato zoato nato
Water 0.018 > 10 0.036 > 10 0.036 0.091
Ethanol 3.68 > 7.94 0.07 > 7.94 0.97 0.27
Isopropan
2. 03 4.51 0.09 2.75 0.35 0.23 ol
Acetone 0.52 0.08 0.06 1.3 0.36 0.09
Octanol 1 -2 1-2 < 0.1
Acetate
0. 45 0.03 0.05 0.31 0.08 0.07 ethyl
regulator
of phosphate < 0.001 < 0.001 < 0.001 pH 6.88
Claims (15)
1. A salt of 2-amino-2- (2- (4-octyl-phenyl) -ethyl) -propane-1,3-diol (FTY720), wherein the salt is selected from the salts of tartrate, lactate, benzoate, succinate, malonate, acetate and propionate, the salt being optionally crystalline.
2. A salt according to claim 1, wherein the salt is selected from the tartrate, lactate, succinate and malonate salts, the salt being optionally crystalline.
3. A salt according to claim 2, wherein the salt is a tartrate salt, which optionally comprises a crystalline form characterized by an X-ray powder diffraction pattern with peaks at about 3.1, 19.3, 21.7, 9.6, 17.2, 6.4, 22.6 and 20.8 degrees 2-theta.
4. A salt according to claim 2, wherein the salt is a lactate salt, which optionally comprises a crystalline form characterized by an X-ray powder diffraction pattern with peaks at about 4.3, 8.7, 20.8, 13.1, 10.3, 18.8, 8.1, 21.6, 21.9 and 19.6 degrees 2-theta.
5. A salt according to claim 2, wherein the salt is a benzoate salt, which optionally comprises a crystalline form characterized by an X-ray powder diffraction pattern with peaks at about 3.7, 7.5, 18.7, 19.8, 15.2, 19.4, 19.9, 6.0 and 21.9 degrees 2-theta.
6. A salt according to claim 2, wherein the salt is a succinate salt, which optionally comprises a crystalline form characterized by an X-ray powder diffraction pattern with peaks at about 3.2, 19.8, 20.7, 23.3, 26.2, 9.8, 19.4, 24.5, 33.4, 26.6 and 22.6 degrees 2-theta.
7. A salt according to claim 2, wherein the salt is a malonate salt, which optionally comprises a crystalline form characterized by an X-ray powder diffraction pattern with peaks at about 2.5, 5.2, 8.0, 16.2, 17.0, 20.4 degrees 2-theta.
8. A salt according to claim 1, wherein the salt is an acetate salt, which optionally comprises a crystalline form characterized by an X-ray powder diffraction pattern with peaks at about 4.8, 8.4, 10.1, 11.5, 15.2, 17.7, 19.3, 20.1, 21.5, 21.9, 24.0, 25.4, 30.8 degrees 2-theta.
9. A salt according to claim 1, wherein the salt is a propionate salt, which optionally comprises a crystalline form characterized by an X-ray powder diffraction pattern with peaks at about 4.8, 8.4, 9.8, 14.7, 16.8, 17.6, 19.7, 20.2, 22.6, 24.8, 29.8 degrees 2-theta.
10. A salt according to any of the preceding claims, which is in a substantially pure crystalline form.
11. A salt of any of the preceding claims, for use in therapy.
12. A salt of any of claims 1 to 10, for used in the treatment or prevention of rejection of organ or tissue transplantation, autoimmune diseases, or inflammatory conditions.
13. A pharmaceutical composition, which comprises a salt of any of claims 1 to 10, together with a pharmaceutically acceptable carrier or excipient.
14. The use of a salt of any of claims 1 to 10, for the manufacture of a medicament for the treatment or prevention of rejection of organ or tissue transplantation, autoimmune diseases, or inflammatory conditions.
15. A method for the treatment or prevention of rejection of organ or tissue transplantation, autoimmune diseases, or inflammatory conditions in a patient, which comprises administering a therapeutically effective amount of a salt of any of claims 1 to 10.
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| PCT/EP2009/064889 WO2010055027A2 (en) | 2008-11-11 | 2009-11-10 | Organic compounds |
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| BRPI0610308A8 (en) | 2005-05-26 | 2017-04-25 | Neuron Systems Inc | COMPOSITIONS AND METHODS FOR THE TREATMENT OF RETINAL DISEASE |
| MX2011004924A (en) * | 2008-11-11 | 2011-05-30 | Novartis Ag | Salts of fingolimod. |
| EP2456752A2 (en) * | 2009-07-24 | 2012-05-30 | ratiopharm GmbH | Process for producing fingolimod salts |
| WO2011072141A1 (en) | 2009-12-11 | 2011-06-16 | Neuron Systems, Inc. | Compositions and methods for the treatment of macular degeneration |
| US8735627B2 (en) | 2010-10-28 | 2014-05-27 | Mapi Pharma Ltd. | Intermediate compounds and process for the preparation of fingolimod |
| WO2012071524A1 (en) | 2010-11-24 | 2012-05-31 | Ratiopharm Gmbh | Arylsulfonate salts of fingolimod and processes for preparation thereof |
| AR085749A1 (en) | 2011-04-01 | 2013-10-23 | Novartis Ag | FORMULATIONS |
| EP2505589A1 (en) | 2011-04-01 | 2012-10-03 | Johann Wolfgang Goethe-Universität Frankfurt am Main | Novel sphingolipid heterocyclic compounds as modulators of sphingolipid signaling and uses thereof |
| CN102887829B (en) * | 2012-09-05 | 2014-07-02 | 中国科学院上海药物研究所 | Method for preparing fingolimod mucate and crystals thereof and application of fingolimod mucate and crystals thereof |
| MX2015009383A (en) | 2013-01-23 | 2016-03-17 | Aldeyra Therapeutics Inc | Toxic aldehyde related diseases and treatment. |
| ES2964891T3 (en) | 2013-03-05 | 2024-04-10 | Biocon Ltd | A process for the preparation of 2-amino-1,3-propanediol compounds and salts thereof |
| US10675254B2 (en) | 2013-10-11 | 2020-06-09 | Teikoku Seiyaku Co., Ltd. | Sphingosine-1-phosphate receptor agonist iontophoretic devices and methods of using the same |
| WO2015053878A1 (en) | 2013-10-11 | 2015-04-16 | Teikoku Pharma Usa, Inc. | Topical sphingosine-1-phosphate receptor agonist formulations and methods of using the same |
| US9925138B2 (en) | 2015-01-20 | 2018-03-27 | Handa Pharmaceuticals, Llc | Stable solid fingolimod dosage forms |
| AU2017264697A1 (en) | 2016-05-09 | 2018-11-22 | Aldeyra Therapeutics, Inc. | Combination treatment of ocular inflammatory disorders and diseases |
| FI3466934T3 (en) | 2016-05-31 | 2024-04-23 | Taiho Pharmaceutical Co Ltd | Sulfonamide compounds or salt thereof as ribonucleotide reductase inhibitors for treating cancer |
| RU2627691C1 (en) * | 2016-07-06 | 2017-08-10 | Олег Ростиславович Михайлов | Crystalline h-modification of 2-amino-2-(2-(4-octylphenyl) ethyl)propane-1,3-diole hydrochloride, method for its production and pharmaceutical composition based thereon |
| MX2020003425A (en) | 2017-10-10 | 2020-07-29 | Aldeyra Therapeutics Inc | Treatment of inflammatory disorders. |
| EP3813835A4 (en) * | 2018-06-29 | 2022-03-02 | Forma Therapeutics, Inc. | Salts of (s)-(5-cyclobutoxy-2-methyl-6-(1-(piperidin-4-yl)-1h-pyrazol-4-yl)-3,4-dihydroquinolin-1(2h)-yl)(cyclopropyl)methanone and solid forms thereof |
| JP2021533154A (en) * | 2018-08-06 | 2021-12-02 | アルデイラ セラピューティクス， インコーポレイテッド | Polymorphic compounds and their use |
| WO2020223717A1 (en) | 2019-05-02 | 2020-11-05 | Aldeyra Therapeutics, Inc. | Process for preparation of aldehyde scavenger and intermediates |
| WO2020223685A1 (en) | 2019-05-02 | 2020-11-05 | Aldeyra Therapeutics, Inc. | Polymorphic compounds and uses thereof |
| JP2023501217A (en) | 2019-10-31 | 2023-01-18 | イドーシア ファーマシューティカルズ リミテッド | Combinations of CXCR7 antagonists with S1P1 receptor modulators |
| CN115697336A (en) | 2020-05-13 | 2023-02-03 | 奥尔德拉医疗公司 | Pharmaceutical preparation and use thereof |
| CN115477590B (en) * | 2021-05-31 | 2023-12-12 | 上海云晟研新生物科技有限公司 | Fengomod medicinal salt, preparation method, pharmaceutical composition containing same and application |
| EP4212156A1 (en) | 2022-01-13 | 2023-07-19 | Abivax | Combination of 8-chloro-n-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its derivatives with a s1p receptor modulator |
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| ECSP951461A (en) | 1995-06-07 | 1998-04-07 | SYNTHESIS OF 3- {4- (2- AMINOETOXI) BENZOIL] -2-ARYL-6- HYDROXYBENZO {b] THIOPHENES (CASE X- 9295B) | |
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| DK1129066T3 (en) * | 1998-11-11 | 2005-03-29 | Novartis Ag | Preparation of 2-amino-2- [2- (C2-20 alkylphenyl) ethyl] propane-1,3-diols |
| JP4627356B2 (en) * | 1999-06-30 | 2011-02-09 | 松森 昭 | Drugs for preventing or treating viral myocarditis |
| RU2003136730A (en) * | 2001-06-08 | 2005-05-20 | Новартис АГ (CH) | TREATMENT OR PREVENTION OF REFUSAL OF AN INSULIN-PRODUCING CELL TRANSPLANT |
| ATE412408T1 (en) * | 2002-05-16 | 2008-11-15 | Novartis Pharma Gmbh | USE OF EDG RECEPTOR BINDING INGREDIENTS FOR CANCER THERAPY |
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| EP2319502A1 (en) | 2003-04-08 | 2011-05-11 | Novartis AG | Solid pharmaceutical compositions comprising a S1P receptor agonist and a sugar alcohol |
| EA012266B1 (en) * | 2004-12-21 | 2009-08-28 | Лаборатуар Сероно С.А. | Sulfonyl amino cyclic derivatives and use thereof |
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| CN101272780A (en) * | 2005-09-30 | 2008-09-24 | 诺瓦提斯公司 | DPP IV inhibitor for use in the treatment of autoimmune diseases and graft rejection |
| ES2414205T3 (en) * | 2006-06-02 | 2013-07-18 | The Ohio State University Research Foundation | Therapeutic agents for the treatment of mantle cell lymphoma |
| WO2009100116A1 (en) * | 2008-02-04 | 2009-08-13 | Medical College Of Georgia Research Institute | Oligodendrocyte precursor cell composition and methods of use |
| MX2011004924A (en) * | 2008-11-11 | 2011-05-30 | Novartis Ag | Salts of fingolimod. |
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| IL212073A0 (en) | 2011-06-30 |
| EP2358660A2 (en) | 2011-08-24 |
| BRPI0921533A2 (en) | 2016-01-12 |
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| US8680146B2 (en) | 2014-03-25 |
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| AU2009315735A1 (en) | 2010-05-20 |
| JP2015178503A (en) | 2015-10-08 |
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